CN114621206A - 一种5-取代的嘧啶二胺类衍生物及其制备方法与应用 - Google Patents
一种5-取代的嘧啶二胺类衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种新的5‑取代的嘧啶二胺类衍生物及其制备方法与应用，涉及药物化学技术领域，所述5‑取代的嘧啶二胺类衍生物结构新颖，药物代谢动力学性质改善，生物利用度显著提高，具有较好的口服可利用性；可用于研究组织蛋白酶C参与的信号通路传导，以及对于体内代谢动力学评价；并且体外和体内抗组织蛋白酶C活性筛选结果显示其对组织蛋白酶C表现出较强的抑制活性，体内急性毒性实验结果表明其具有较高的安全性，体内药效学实验结果显示其对中性粒细胞丝氨酸蛋白酶较强的抑制活性，体内抗炎活性筛选结果显示其对炎症疾病模型(LPS诱导的急性肺损伤动物模型)有效的治疗作用；同时合成工艺简单，最终产品纯度高，具有良好的应用前景。
Description
技术领域：
本发明涉及药物化学技术领域，具体涉及一种5-取代的嘧啶二胺类衍生物及其制备方法与应用。
背景技术：
在囊性纤维化(CF)、支气管扩张、急性肺损伤(ALI)和慢性阻塞性肺病(COPD)等慢性炎症性肺病中，炎症过度，气道中存在炎症细胞异常增加，尤其是多形核中性粒细胞(PMN)。PMN对于保护免受入侵病原体至关重要，并且是炎症反应的主要介质。在炎症期间，中性粒细胞从血液迁移到受损组织，在那里它们释放储存在其初级颗粒中的中性粒细胞丝氨酸蛋白酶(NSPs)：人中性粒细胞弹性蛋白酶(NE)、蛋白酶3(PR3)、组织蛋白酶G(Cat G)和中性粒细胞丝氨酸蛋白酶4(NSP4)。NSPs参与细胞内和细胞外的非氧化途径破坏病原体，在先天免疫系统中发挥着关键作用。但是，如果不受管制，它们的作用可能是有害的，并导致宿主组织降解。NSPs受到组织蛋白酶C(Cathepsin C)，也称为二肽基肽酶1(DPP1,CTSC,EC3.4.14.1)的调控。
组织蛋白酶C，是一种重要的溶酶体半胱氨酸蛋白酶，来自木瓜蛋白酶家族。组织蛋白酶C通过介导中性粒细胞丝氨酸蛋白酶(NSPs)的成熟过程，参与多形核中性粒细胞相关的炎症和免疫调节过程。因此，组织蛋白酶C是治疗炎症性疾病和自身免疫性疾病的有效靶标。
在中性粒细胞成熟的早期，NSPs被合成为在氨基末端含有二肽结构的惰性酶原形式。NSP酶原被组织蛋白酶C激活后，成熟的NSPs与髓过氧化物酶和NADPH氧化酶复合物产生的活性氧结合以帮助降解吞噬溶酶体内的病原微生物。在某些疾病状态下，由嗜中性粒细胞的积累和活化引起的活性NSPs的过度分泌会导致组织损伤和炎症。NSPs参与多种炎性疾病的进展，例如败血症，急性胰腺炎，类风湿性关节炎，抗中性粒细胞胞浆抗体相关的坏死性新月形肾小球肾炎，COPD，支气管扩张，CF和ALI。此外，最新的证据指出，NSPs分泌到细胞外会导致嗜中性粒细胞胞外陷阱的形成，该现象被认为是严重COVID-19的驱动因素。因此，NSPs被认为是包括COVID-19在内的嗜中性粒细胞相关炎症性疾病治疗有希望的生物学靶标。组织蛋白酶C是通过介导NSPs的成熟来参与调节炎症和免疫过程的。因此，通过靶向组织蛋白酶C发挥抗炎作用的药物必须能够影响体内NSPs的活性。
组织蛋白酶C抑制剂的开发已经历了30多年，只有硕果仅存的brensocatib(AZD7986)顺利进入III期临床试验。几乎所有报道的组织蛋白酶C抑制剂都含有能与Cys234形成共价键的“战斗部”。亲电子“战斗部”基团通常可以提高针对目标的选择性和效率。但是有时，这些组织蛋白酶C抑制剂的肽性质和亲电子性质与不良代谢稳定性有关。亲电子“战斗部”基团的高反应性有时可能导致选择性差、脱靶效应，这可能带来潜在的安全隐患。这些问题是药物开发中的严重障碍，也可能是组织蛋白酶C抑制剂在临床药物开发中未取得重大进展的主要原因。
由于Cat C抑制剂或催化底物的结合位点相对较浅，大多数药物化学家认为非共价抑制剂与Cat C的相互作用有限，不适合小分子Cat C抑制剂的开发。我们对此观点保留意见，因为我们认为非共价抑制剂也可以有效的抑制体内外Cat C的生物活性。不仅如此，作为Cat C抑制剂的两个重要构成要素：共价亲电“弹头”结构和肽基结构，有时却会导致选择性差和随后的脱靶效应，埋下了代谢稳定性和安全性的隐患，这也解释了为何Cat C抑制剂研究多年却始终在临床应用中没有取得重大进展。因此，为了避免肽基共价衍生物的缺陷，探讨具有新型作用机制的Cat C抑制剂开发的可能性，我们提出了“非肽基-非共价CatC抑制剂”的概念，并已经取得了一定的成果。
本发明以先前申请的专利CN112920124A中具有独特噻吩取代吡啶结构的化合物64(5-氯-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺)为先导，并通过基于结构的药物化学优化，确定了一系列结构新颖的5-取代的嘧啶二胺类衍生物，并进一步扩充了已有的非肽基-非共价Cat C抑制剂小分子化合物库，证明了非肽基-非共价Cat C抑制剂具有广阔的应用前景。研究发现，本发明中的化合物38不仅继续保持对CatC很强的抑制活性(IC50＝59.9nM)，还具有较好的体外代谢稳定性(HLM CLint＝6.3)，同时具有较好的药物代谢动力学(PK)特征，生物利用度显著提高(F＝47.3％)，明显优于专利CN112920124A中对Cat C抑制活性最好的化合物41(F＝16.7％)。
发明内容：
本发明所要解决的技术问题在于提供一种5-取代的嘧啶二胺类衍生物及其制备方法，该类化合物作为一类“非肽衍生物非共价组织蛋白酶C抑制剂”，可以应用于制备预防或治疗NSP相关疾病的药物中。
本发明所要解决的技术问题采用以下的技术方案来实现：
一种5-取代的嘧啶二胺类衍生物，如式I所示：
其中，R1选自取代苯基、取代苄基、吡啶基、哌啶基中的任一种基团；
R2选自苯基、吡啶基、取代吡啶基、嘧啶基、吡嗪基、哒嗪基中的任一种基团；
R3选自呋喃基或噻吩基；
R4选自氯、溴、呋喃、1-甲基-1H-吡唑-4-基、1-甲基-1,2,3,6-四氢吡啶-4-基、吡啶基、苯基、取代苯基中的任一种基团。
所述5-取代的嘧啶二胺类衍生物包括结构如下所示的化合物1-40：
所述5-取代的嘧啶二胺类衍生物的制备方法，包括以下步骤：
(1)将C5取代的2,4-二氯嘧啶类化合物和R1-NH2在四丁基碘化铵或者NaH催化下发生亲核取代反应，得到中间体I；
(2)化合物Br-R2-NH2和噻吩硼酸或呋喃硼酸发生铃木反应，得到中间体II；
(3)中间体I和中间体II经布赫瓦尔德-哈特维希反应，得到本发明的化合物1、18-40；
(4)本发明的化合物1或专利CN112920124A中的化合物64和不同取代的硼酸发生铃木反应，得到本发明的化合物2-17；
反应方程式如下：
一种药物组合物，包含上述5-取代的嘧啶二胺类衍生物或其药学上可接受的盐。
一种药物制剂，包含活性成分和药学上可以接受的赋形剂和/或载体，所述活性成分为上述5-取代的嘧啶二胺类衍生物。
上述5-取代的嘧啶二胺类衍生物在制备调控组织蛋白酶催化活性制剂中的应用。进一步地，所述组织蛋白酶为组织蛋白酶C。
上述5-取代的嘧啶二胺类衍生物在制备治疗NSP相关疾病药物中的应用。进一步地，所述NSP相关疾病选自急性肺损伤、囊性纤维化和支气管扩张等呼吸系统慢性炎症以及关节炎、类风湿性关节炎、败血症、急性胰腺炎、肾炎等其他炎症与自身免疫性疾病。
本发明的有益效果是：
(1)本发明的5-取代的嘧啶二胺类衍生物结构新颖，与专利CN112920124A相比，药物代谢动力学性质改善，生物利用度显著提高，具有较好的口服可利用性；
(2)本发明的5-取代的嘧啶二胺类衍生物可用于研究组织蛋白酶C参与的信号传导通路，以及对于新型组织蛋白酶C抑制剂的评价，同时对体内药物代谢动力学的研究评价；
(3)本发明的5-取代的嘧啶二胺类衍生物经体外抗组织蛋白酶C活性筛选，结果显示其与专利CN112920124A相比对组织蛋白酶C表现出相当的抑制活性，同时毒性较低；
(4)本发明的5-取代的嘧啶二胺类衍生物经体内抗组织蛋白酶C活性筛选，结果显示其对组织蛋白酶C表现出较强的抑制活性，同时细胞毒性较低；
(5)本发明的5-取代的嘧啶二胺类衍生物经体内急性毒性实验结果表明其毒性低，具有较高的安全性；
(6)本发明的5-取代的嘧啶二胺类衍生物经体内药效学实验结果显示其对中性粒细胞丝氨酸蛋白酶较强的抑制活性，同时毒性较低；
(7)本发明的5-取代的嘧啶二胺类衍生物经体内抗炎活性筛选，结果显示其对炎症疾病模型(LPS诱导的急性肺损伤动物模型)有效的治疗作用，同时毒性较低，代谢稳定性好；
(8)本发明所述的5-取代的嘧啶二胺类衍生物结构新颖、合成工艺简单、产品纯度高，具有良好的应用前景。
附图说明：
图1为本发明的化合物38对正常小鼠体内组织蛋白酶C和下游NSPs的抑制作用；
图2为本发明的化合物38在大鼠口服(10mg/kg)给药后的血浆浓度与时间曲线；
图3为本发明的化合物38在模型组对急性肺损伤模型小鼠体内组织蛋白酶C和下游NSPs的抑制作用；
图4为本发明的化合物38对急性肺损伤模型小鼠体内炎症因子的影响。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例和图示，进一步阐述本发明。
实施例1
N-(3-((2,5-二氯嘧啶-4-基)氨基)苯基)乙酰胺(中间体I-1)的合成：
称取0.5g 2,4,5-三氯嘧啶(2.73mmol)加入到50mL圆底烧瓶中，并以5mL二甲基亚砜溶解，然后加入催化量的四丁基碘化铵，搅拌5min。待溶液由无色变为黄色后加入0.38g间乙酰氨基苯胺(2.50mmol)和0.32g无水碳酸钠(3.00mmol)，在室温下搅拌3h。用薄层色谱法(石油醚:乙酸乙酯＝10:1)检测反应终点。待反应结束后，用25mL冰水淬灭反应并搅拌30min后，用乙酸乙酯萃取(3次，每次30mL)混合物。合并萃取的乙酸乙酯层，用饱和氯化钠溶液洗涤三次。乙酸乙酯层用无水硫酸钠干燥24h后过滤并浓缩乙酸乙酯层，得到的残留物用自动化中压色谱纯化系统进行纯化分离。产物为白色固体；产率为82％(0.6g)。
5-(噻吩-3-基)吡啶-2-胺(中间体II-1)的合成：
称取0.23g 5-溴吡啶-2-胺(1.30mmol)、0.2g 3-噻吩硼酸(1.56mmol)、0.09g(PPh3)2PdCl2(0.13mmol)和0.49g Na2CO3(4.68mmol)加入到35mL封管中，加入二氧六环(6mL)和水(2mL)，氩气保护下在110℃条件下搅拌反应10h。反应完毕，反应混合液经硅藻土过滤后直接浓缩拌样，经自动色谱系统纯化，产物为白色固体；产率为79％。
N-(3-((5-氯-2-((5-(噻吩-3-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(化合物38)的合成：
取35mL封管以氩气进行气体置换，取0.12g中间体I-1(0.40mmol)、0.06g中间体II-1(0.34mmol)、12mg Pd2(dba)3(0.013mmol)、17mg BINAP(0.027mmol)和38mg NaOtBu(0.5mmol)加入到封管中，以8mL无水二氧六环搅拌溶解。密封封管并在110℃下反应12h。反应毕，冷却至室温，将反应混合物通过硅藻土垫过滤，滤液浓缩后用乙酸乙酯(30mL)稀释并继续用水和饱和氯化钠溶液洗涤。乙酸乙酯层用无水硫酸钠干燥24h后过滤并浓缩乙酸乙酯层，得到的残留物用自动化中压色谱纯化系统进行纯化分离，获得白色固体；产率54％(0.08g)。mp 263-264℃；1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.75(s,1H),9.06(s,1H),8.67(s,1H),8.25(s,1H),8.08(d,J＝8.8Hz,1H),7.96(s,1H),7.85(s,1H),7.80(d,J＝8.6Hz,1H),7.66(t,J＝4.0Hz,1H),7.56(d,J＝5.0Hz,1H),7.44(d,J＝6.9Hz,1H),7.33(d,J＝7.0Hz,2H),2.01(s,3H).13C NMR(101MHz,DMSO-d6)δ168.26,156.56,156.17,154.71,151.74,145.19,139.36,138.66,138.33,134.71,128.58,127.33,125.71,124.72,120.14,118.60,115.33,114.74,112.56,105.19,24.03.HRMS(ESI)m/z:[M+H]+calcd forC21H17ClN6OS:437.0946；found:437.0943.
实施例2
5-溴-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物1)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-2。White solid(yield:64％).mp220-221℃；1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.99(s,1H),8.66(s,1H),8.37(s,1H),8.25(d,J＝8.2Hz,1H),8.07–7.80(m,4H),7.75–7.41(m,4H).13C NMR(101MHz,DMSO-d6)δ157.94,157.08,156.51,151.66,145.26,139.52,138.29,134.80,129.57,129.17(d,J＝32.3Hz),127.30,126.82,125.73,124.87,124.17(d,J＝273.7Hz),120.25,120.14,119.15,112.66,94.43.HRMS(ESI)m/z:[M+H]+calcd for C20H13BrF3N5S:492.0100；found:492.0101.
实施例3
5-(呋喃-3-基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物2)的合成：
将3-呋喃硼酸(0.45mmol,51mg)、Pd(PPh3)4(0.056mmol,65mg)、PCy3(0.22mmol,65mg)和K2CO3(0.80mmol,0.12g)加入到化合物64(0.22mmol,0.1g)或化合物1(0.22mmol,0.11g)的1,4-二氧六环/水(6mL/2mL)混合溶液中。在氩气保护下，将封管密封，并将混合液在110℃下加热反应10h。冷却至室温后，将反应混合物通过硅藻土垫过滤，滤液浓缩后用乙酸乙酯(50mL)稀释并继续用水和饱和氯化钠溶液洗涤。有机相用无水硫酸钠干燥过夜后浓缩，残留物经自动色谱系统纯化，得到0.09g白色固体(产率：85％)。mp 189-190℃；1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.67(d,J＝2.4Hz,1H),8.60(s,1H),8.30–8.22(m,2H),8.11(d,J＝8.7Hz,1H),8.05(s,1H),7.96–7.83(m,4H),7.66(dd,J＝5.1,2.9Hz,1H),7.58(dd,J＝9.5,6.5Hz,2H),7.40(d,J＝7.8Hz,1H),6.83(d,J＝1.8Hz,1H).13C NMR(101MHz,DMSO)δ157.65,157.27,156.21,152.01,145.30,143.93,140.80,140.39,138.42,134.90,129.48,129.12(d,J＝31.3Hz),127.35,126.05,125.78,124.64,124.31(d,J＝272.7Hz),120.17,119.17,118.28,118.22,112.52,110.95,104.81.HRMS(ESI)m/z:[M+H]+calcd forC24H16F3N5OS:480.1100；found:480.1272.
实施例4
5-(1-甲基-1H-吡唑-4-基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物3)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为(1-甲基-1H-吡唑-4-基)硼酸。Whitesolid(yield:52％).mp 199-200℃；1H NMR(400MHz,DMSO-d6)δ9.72(d,J＝8.4Hz,1H),8.66(d,J＝2.4Hz,1H),8.58(s,1H),8.29(d,J＝8.3Hz,1H),8.16(s,1H),8.12(d,J＝8.7Hz,1H),8.03(s,1H),7.94(s,1H),7.90(dd,J＝8.7,2.5Hz,1H),7.86(d,J＝1.5Hz,1H),7.70(s,1H),7.66(dd,J＝5.0,2.9Hz,1H),7.61–7.54(m,2H),7.39(d,J＝7.7Hz,1H),3.92(s,3H).13C NMR(101MHz,DMSO-d6)δ157.65,156.94,155.92,152.06,145.24,140.45,138.41,138.04,134.93,130.08,129.44,128.77(q,J＝32.3Hz),127.32,125.91,125.76,124.54,124.31(d,J＝273.7Hz),120.12,119.01,118.11,113.50,112.43,105.45,38.74.HRMS(ESI)m/z:[M+H]+calcd for C24H18F3N7S:494.1369；found:494.0784.
实施例5
5-(1-甲基-1,2,3,6-四氢吡啶-4-基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基))嘧啶-2,4-二胺(化合物4)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为(1-甲基-1,2,3,6-四氢吡啶-4-基)硼酸。White solid(yield:68％).mp 185-186℃；1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.65(d,J＝2.4Hz,1H),8.58(s,1H),8.26(d,J＝8.4Hz,1H),8.11(d,J＝8.8Hz,1H),8.01(s,1H),7.95–7.84(m,3H),7.66(dd,J＝5.1,2.9Hz,1H),7.60–7.53(m,2H),7.39(d,J＝7.7Hz,1H),5.86(s,1H),3.05(d,J＝3.1Hz,2H),2.62(t,J＝5.6Hz,2H),2.38(d,J＝6.5Hz,2H),2.31(s,3H).13C NMR(101MHz,DMSO-d6)δ157.27,157.03,155.29,152.07,145.25,140.37,138.44,134.84,129.45,129.35,129.08(d,J＝31.3Hz),127.29,126.46,126.01,125.75,124.50,124.30(d,J＝273.7Hz),120.06,119.01,118.13(d,J＝4.0Hz),114.40,112.33,54.25,51.39,45.40,29.21.HRMS(ESI)m/z:[M+H]+calcd for C26H23F3N6S:509.1730；found:509.2162.
实施例6
5-(吡啶-4-基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物5)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为(吡啶-4-基)硼酸。White solid(yield:44％).mp 290-291℃；1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.94(s,1H),8.67(dd,J＝10.3,3.8Hz,3H),8.22(d,J＝6.8Hz,2H),8.11(d,J＝8.7Hz,1H),7.92–7.84(m,3H),7.69–7.65(m,1H),7.58(m,4H),7.41(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.97,157.42,157.33,151.80,150.12(2C),145.29,142.67,140.27,138.34,134.84,129.49,129.08(d,J＝31.3Hz),127.32,126.20,125.76,124.87,124.24(d,J＝272.7Hz),123.74(2C),120.25,119.28,118.30,112.76,110.82.HRMS(ESI)m/z:[M+H]+calcd forC25H17F3N6S:491.1260；found:491.0685.
实施例7
5-苯基-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物6)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为苯硼酸。White solid(yield:77％).mp170-171℃；1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.77–8.63(m,2H),8.23(d,J＝8.3Hz,1H),8.16–8.07(m,2H),7.95–7.82(m,3H),7.67(dd,J＝5.0,2.9Hz,2H),7.60–7.47(m,5H),7.43(d,J＝6.4Hz,1H),7.39(d,J＝8.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.64,157.30,156.68,152.02,145.26,140.41,138.41,134.95,134.55,129.45,129.11(4C),129.07(d,J＝32.3Hz),127.66,127.35,126.14,125.78,124.67,124.30(d,J＝273.7Hz),120.19,119.15,118.30,113.51,112.53.HRMS(ESI)m/z:[M+H]+calcd for C26H18F3N5S:490.1308；found:490.1309.
实施例8
5-(4-氯苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物7)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-氯苯硼酸。White solid(yield:65％).mp207-208℃；1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.74(s,1H),8.68(s,1H),8.25(d,J＝8.3Hz,1H),8.17–8.10(m,2H),7.93–7.84(m,3H),7.66(dd,J＝5.0,2.9Hz,1H),7.59-7.50(m,6H),7.39(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.57,157.54,156.79,151.95,145.27,140.36,138.38,134.86,133.50,132.35,131.07(2C),129.42,129.01(2C),128.73(q,J＝32.3Hz),127.29,126.03,125.74,124.69,124.26(d,J＝273.7Hz),120.15,119.10(d,J＝3.0Hz),118.19,112.54,112.34.HRMS(ESI)m/z:[M+H]+calcd for C26H17ClF3N5S:524.0918；found:524.1321.
实施例9
5-(3-氯苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物8)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为3-氯苯硼酸。White solid(yield:20％).mp94-95℃；1H NMR(400MHz,DMSO-d6)δ9.91(d,J＝4.0Hz,1H),8.81(s,1H),8.68(d,J＝2.4Hz,1H),8.24(d,J＝8.3Hz,1H),8.13(d,J＝7.8Hz,2H),7.92–7.86(m,3H),7.67(dd,J＝5.0,2.9Hz,1H),7.61–7.49(m,3H),7.43–7.33(m,3H),7.25(td,J＝8.7,2.6Hz,1H).13CNMR(101MHz,DMSO-d6)δ157.86,157.49,157.32,156.52,152.05,145.30,140.44,138.43,135.65,134.88,130.19,129.44,129.07(d,J＝31.3Hz),127.32,125.97,125.78,124.62,124.30(d,J＝273.7Hz),120.14,119.67,119.03,118.13,115.82,114.77,113.58,112.49.HRMS(ESI)m/z:[M+H]+calcd for C26H17ClF3N6S:524.0918；found:524.1394.
实施例10
4-(2-((5-(噻吩-3-基)吡啶-2-基)氨基)-4-((3-(三氟甲基)苯基)氨基)嘧啶-5-基)苯甲酰胺(化合物9)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-氨基甲酰基苯硼酸。White solid(yield:36％).mp 265-266℃；1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.81(s,1H),8.67(d,J＝2.4Hz,1H),8.24(d,J＝8.4Hz,1H),8.15(s,1H),8.12(d,J＝8.7Hz,1H),8.06(s,1H),8.02(d,J＝8.0Hz,2H),7.92(d,J＝8.6Hz,1H),7.87(s,2H),7.69–7.65(m,1H),7.64–7.54(m,4H),7.40(d,J＝8.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ167.50,157.60,157.50,156.82,151.92,145.20,140.35,138.32,137.55,135.02,133.18,129.45,128.91(t,J＝32.3Hz),128.90(2C),128.23(2C),127.35,126.14,125.75,124.76,124.27(d,J＝273.7Hz),120.26,119.20,118.30,112.89,112.71.HRMS(ESI)m/z:[M+H]+calcd forC27H19F3N6OS:533.1366；found:533.0754.
实施例11
3-(2-((5-(噻吩-3-基)吡啶-2-基)氨基)-4-((3-(三氟甲基)苯基)氨基)嘧啶-5-基)苯甲酰胺(化合物10)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为3-氨基甲酰基苯硼酸。Grey solid(yield:36％).mp 267-268℃；1H NMR(400MHz,DMSO-d6)δ9.83(d,J＝5.3Hz,1H),8.76(s,1H),8.68(s,1H),8.23(d,J＝8.4Hz,1H),8.14(d,J＝11.0Hz,2H),8.04(d,J＝12.5Hz,2H),7.96–7.84(m,4H),7.67(d,J＝5.9Hz,2H),7.59(m,3H),7.46–7.37(m,2H).13C NMR(101MHz,DMSO)δ167.66,157.61,157.52,157.07,151.97,145.29,140.39,138.39,134.93,134.85,134.61,131.98,129.41,129.05(d,J＝31.3Hz),129.00,128.20,127.29,126.80,126.21,125.74,124.67,124.26(d,J＝273.7Hz),120.14,119.13,118.32,112.95,112.52.HRMS(ESI)m/z:[M+H]+calcd for C27H19F3N6OS:533.1366；found:533.0760.
实施例12
N-(4-(2-((5-(噻吩-3-基)吡啶-2-基)氨基)-4-((3-(三氟甲基)苯基)氨基)嘧啶-5-基)苯基)乙酰胺(化合物11)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-乙酰氨基苯硼酸。White solid(yield:70％).mp 259-260℃；1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.79(s,1H),8.70–8.62(m,2H),8.25(d,J＝8.3Hz,1H),8.15(d,J＝8.8Hz,1H),8.09(s,1H),7.92–7.84(m,3H),7.72(d,J＝8.2Hz,2H),7.68–7.63(m,1H),7.56(t,J＝6.6Hz,2H),7.44(d,J＝8.2Hz,2H),7.38(d,J＝7.8Hz,1H),2.08(s,3H).13C NMR(101MHz,DMSO-d6)δ168.36,157.62,157.20,156.59,152.04,145.27,140.44,138.92,138.42,134.86,129.47(2C),129.39,128.85,128.72(q,J＝32.3Hz),127.28,125.98,125.74,124.57,124.27(d,J＝272.7Hz),120.09,119.45(2C),118.99,118.16(d,J＝2.0Hz),113.30,112.43,24.06.HRMS(ESI)m/z:[M+H]+calcd for C28H21F3N6OS:547.1522；found:547.0902.
实施例13
N-(3-(2-((5-(噻吩-3-基)吡啶-2-基)氨基)-4-((3-(三氟甲基)苯基)氨基)嘧啶-5-基)苯基)乙酰胺(化合物12)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为3-乙酰氨基苯硼酸。White solid(yield:72％).mp 208-209℃；1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.84(s,1H),8.72–8.66(m,2H),8.25(d,J＝8.3Hz,1H),8.15(d,J＝8.8Hz,1H),8.12(s,1H),7.91(q,J＝2.8Hz,2H),7.87(d,J＝2.8Hz,1H),7.72(d,J＝8.3Hz,1H),7.67(d,J＝5.7Hz,2H),7.58(q,J＝7.1,6.1Hz,2H),7.46–7.37(m,2H),7.18(d,J＝7.6Hz,1H),2.06(s,3H).13C NMR(101MHz,DMSO-d6)δ168.43,157.46,157.41,156.66,151.99,145.30,140.37,139.93,138.41,134.86,134.83,129.52,129.43,129.23,128.76(d,J＝31.3Hz),127.29,126.02,125.75,124.65,123.70,122.91(t,J＝273.7Hz),120.13,119.38,119.09,118.16(t,J＝5.1Hz),113.32,112.53,24.06.HRMS(ESI)m/z:[M+H]+calcd for C28H21F3N6OS:547.1522；found:547.0908.
实施例14
1-(3-(2-((5-(噻吩-3-基)吡啶-2-基)氨基)-4-((3-(三氟甲基)苯基)氨基)嘧啶-5-基)苯基)乙烷(化合物13)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为3-乙酰苯基硼酸。White solid(yield:68％).mp 216-217℃；1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.79(s,1H),8.69(d,J＝2.4Hz,1H),8.22(d,J＝8.4Hz,1H),8.17(s,1H),8.15(d,J＝8.8Hz,1H),8.09(s,1H),7.99(d,J＝7.8Hz,1H),7.90(dd,J＝8.8,2.5Hz,1H),7.87(s,2H),7.78(d,J＝7.6Hz,1H),7.69–7.62(m,2H),7.58(q,J＝6.7,6.1Hz,2H),7.40(d,J＝7.7Hz,1H),2.64(s,3H).13C NMR(101MHz,DMSO-d6)δ197.99,157.66,157.62,157.13,151.97,145.30,140.36,138.40,137.50,135.14,134.86,133.96,129.45,129.20,129.16,128.73(q,J＝31.3Hz),127.32,127.19,126.26,125.76,124.70,124.26(d,J＝272.7Hz),120.17,119.21,118.35,112.64,112.56,26.92.HRMS(ESI)m/z:[M+H]+calcd for C28H20F3N5OS:532.1413；found:532.0803.
实施例15
5-(4-(甲基磺酰基)苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物14)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-甲基磺酰基苯硼酸。White solid(yield:55％).mp 283-284℃；1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.94(s,1H),8.69(d,J＝2.4Hz,1H),8.25–8.17(m,2H),8.13(d,J＝8.8Hz,1H),8.03(d,J＝8.1Hz,2H),7.92–7.80(m,5H),7.67(dd,J＝5.0,2.9Hz,1H),7.59(t,J＝7.5Hz,2H),7.41(d,J＝7.7Hz,1H),3.28(s,3H).13C NMR(101MHz,DMSO-d6)δ157.82,157.53,157.34,151.84,145.30,140.31,140.29,139.51,138.35,134.85,129.88(2C),129.46,129.07(d,J＝31.3Hz),127.63(2C),127.31,126.16,125.75,124.82,124.24(d,J＝272.7Hz),120.22,119.23,118.27,112.69,111.93,43.58.FTMS(ESI):(m/z)calcd C27H20F3N5O2S2(M+H):568.106810；found:568.106807.
实施例16
5-(4-氨基苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物15)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-氨基苯硼酸。White solid(yield:55％).mp 110-111℃；1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.65(d,J＝2.4Hz,1H),8.52(s,1H),8.25(d,J＝9.2Hz,1H),8.12(d,J＝8.7Hz,1H),8.01(s,1H),7.92–7.84(m,3H),7.67(dd,J＝5.0,2.9Hz,1H),7.56(dd,J＝9.9,6.4Hz,2H),7.37(d,J＝7.8Hz,1H),7.16(d,J＝8.1Hz,2H),6.69(d,J＝8.1Hz,2H),5.32(s,2H).13C NMR(101MHz,DMSO-d6)δ157.74,156.43,152.10,148.54,147.01,145.15,140.45,138.42,134.95,129.72(2C),129.40,129.07(d,J＝31.3Hz),128.35,127.30,125.75,125.64,124.50,124.29(d,J＝273.7Hz),120.77,120.08,118.92,118.03,114.39(2C),112.32.HRMS(ESI)m/z:[M+H]+calcd forC26H19F3N6S:505.1417；found:505.1418.
实施例17
5-(4-(4-甲基哌嗪-1-基)苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物16)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-(4-甲基哌嗪-1-基)苯硼酸。Whitesolid(yield:75％).mp 125-126℃；1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.66(d,J＝2.5Hz,1H),8.57(s,1H),8.27(d,J＝8.1Hz,1H),8.15(d,J＝8.7Hz,1H),8.05(s,1H),7.93–7.83(m,3H),7.66(dd,J＝5.0,2.9Hz,1H),7.56(dd,J＝11.1,6.3Hz,2H),7.40–7.32(m,3H),7.05(d,J＝8.5Hz,2H),3.21(t,J＝4.9Hz,4H),2.47(t,J＝5.0Hz,4H),2.23(s,3H).13CNMR(101MHz,DMSO-d6)δ157.60,156.95,156.33,152.09,150.37,145.24,140.51,138.44,134.83,129.68(2C),129.38,129.01(d,J＝36.4Hz),128.89,127.27,125.74,124.49(d,J＝280.8Hz),124.17,120.04,118.79,117.90,115.61(2C),115.32,113.63,112.34,54.64(2C),47.76(2C),45.77.FTMS(ESI):(m/z)calcd C31H28F3N7S(M+H):588.213930；found:588.213929.
实施例18
5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物17)的合成：
合成步骤同实施例3，仅将3-呋喃硼酸替换为4-((4-甲基哌嗪-1-基)甲基)苯硼酸。White solid(yield:69％).mp 180-181℃；1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.70(s,1H),8.67(d,J＝2.4Hz,1H),8.22(d,J＝8.3Hz,1H),8.14(d,J＝8.8Hz,1H),8.11(s,1H),7.88(td,J＝7.6,6.3,2.6Hz,3H),7.67(dd,J＝5.0,2.9Hz,1H),7.60–7.53(m,2H),7.47(d,J＝7.8Hz,2H),7.43–7.35(m,3H),3.49(s,2H),2.48–2.21(m,8H),2.15(s,3H).13CNMR(101MHz,DMSO-d6)δ157.60,157.33,156.90,152.05,145.31,140.45,138.44,137.77,134.87,133.10,129.49(2C),129.43,129.01(d,J＝31.3Hz),128.83(2C),127.33,126.11,125.78,124.61,124.30(d,J＝273.7Hz),120.14,119.08,118.26,113.30,112.47,61.93,54.79(2C),52.71(2C),45.82.FTMS(ESI):(m/z)calcd C32H30F3N7S(M+H):602.229370；found:602.229368.
实施例19
5-氯-N2-(4-(噻吩-3-基)苯基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物18)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-2。Grey solid(yield:29％).mp 199-200℃；1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),9.15(s,1H),8.23(s,1H),8.14(d,J＝8.2Hz,1H),7.97(s,1H),7.70(dd,J＝2.9,1.4Hz,1H),7.66–7.58(m,4H),7.54–7.45(m,4H).13C NMR(101MHz,DMSO-d6)δ157.53,155.76,155.17,141.43,139.56,139.30,129.56,129.28(d,J＝32.3Hz),128.49,126.83,126.61,126.08(2C),125.93,124.17(d,J＝273.7Hz),120.10,119.23(2C),119.21,119.10,104.20.HRMS(ESI)m/z:[M+H]+calcd for C21H14ClF3N4S:447.0653；found:447.0654.
实施例20
5-氯-N2-(6-(噻吩-3-基)吡啶-3-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物19)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-3。White solid(yield:33％).mp 180-181℃；1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.23(s,1H),8.72(d,J＝2.6Hz,1H),8.26(s,1H),8.12(d,J＝11.6Hz,1H),8.10–8.02(m,1H),7.99(dd,J＝3.0,1.3Hz,1H),7.96(s,1H),7.69–7.56(m,4H),7.48(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.45,155.84,155.17,146.04,141.92,140.59,139.46,135.46,129.57,129.32(q,J＝32.3Hz),126.74,126.55,126.33,126.06,124.12(d,J＝272.7Hz),121.99,120.18,119.57,119.10(d,J＝4.0Hz),104.87.HRMS(ESI)m/z:[M+H]+calcd for C20H13 ClF3N5S:448.0605；found:448.0604.
实施例21
5-氯-N2-(5-(噻吩-3-基)嘧啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物20)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-4。White solid(yield:36％).mp 186-187℃；1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.16(s,1H),9.02(s,2H),8.83(dd,J＝8.3,2.2Hz,1H),8.33(s,1H),8.22(s,1H),8.05(dd,J＝2.9,1.4Hz,1H),7.74(dd,J＝5.0,2.9Hz,1H),7.68(dd,J＝5.0,1.4Hz,1H),7.64(t,J＝8.0Hz,1H),7.36(d,J＝8.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.36,156.15,155.20(2C),155.18,155.13,139.73,135.24,129.58,129.00(d,J＝32.3Hz),127.70,125.51,125.08,124.25(d,J＝273.7Hz),122.59,121.07,119.12,117.14,106.78.HRMS(ESI)m/z:[M+H]+calcd for C19H12ClF3N6S:449.0558；found:449.0557.
实施例22
5-氯-N2-(5-(噻吩-3-基)吡嗪-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物21)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-5。White solid(yield:32％).mp 243-244℃；1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.27(d,J＝2.8Hz,1H),8.32(d,J＝5.3Hz,1H),8.31(s,1H),8.24(dd,J＝9.4,1.8Hz,1H),8.21–8.18(m,1H),8.00(d,J＝2.4Hz,1H),7.93(d,J＝9.4Hz,1H),7.80(dd,J＝5.2,1.6Hz,1H),7.70(dd,J＝4.8,2.2Hz,1H),7.61(t,J＝8.1Hz,1H),7.46(d,J＝7.7Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.62,155.76,155.03,154.97,150.76,139.39,138.84,129.64,129.20(d,J＝32.3Hz),127.45,126.40,125.80,125.01,124.15(d,J＝273.7Hz),123.77,120.07,118.70,118.43,106.23.HRMS(ESI)m/z:[M+H]+calcd for C19H12ClF3N6S:449.0558；found:449.0560.
实施例23
5-氯-N2-(6-(噻吩-3-基)哒嗪-3-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物22)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-6。White solid(yield:25％).mp 242-243℃；1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.27(s,1H),9.19(d,J＝1.6Hz,1H),8.84(d,J＝1.5Hz,1H),8.35–8.29(m,2H),8.13(dd,J＝3.0,1.3Hz,1H),8.03(t,J＝2.1Hz,1H),7.74(dd,J＝5.1,1.3Hz,1H),7.67(dd,J＝5.1,2.9Hz,1H),7.59(t,J＝8.0Hz,1H),7.46(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.33,155.75,155.06,147.89,141.68,139.40,139.01,138.90,135.19,129.62,129.27(d,J＝32.3Hz),127.30,126.19,125.71,124.13(d,J＝272.7Hz),122.78,120.03,118.66(d,J＝4.0Hz),106.12.HRMS(ESI)m/z:[M+H]+calcd for C19H12ClF3N6S:449.0558；found:449.0553.
实施例24
5-氯-N2-(3-硝基-5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物23)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-7。Yellow solid(yield:20％).mp 190-191℃；1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.22(s,1H),9.07(d,J＝2.2Hz,1H),8.56(d,J＝2.0Hz,1H),8.22(s,1H),8.18–8.10(m,2H),7.99(s,1H),7.73(q,J＝3.4,2.8Hz,2H),7.49(t,J＝8.0Hz,1H),7.38(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.16,155.38,154.85,149.63,143.83,139.26,137.03,136.07,130.85,129.37,129.03(d,J＝31.3Hz),127.82,126.52,125.97,125.40,124.10(d,J＝273.7Hz),122.71,119.76,117.88(d,J＝4.0Hz),106.79.HRMS(ESI)m/z:[M+H]+calcd for C20H12ClF3N6O2S:493.0456；found:493.0451.
实施例25
5-氯-N2-(5-(噻吩-2-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物24)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-8。White solid(yield:36％).mp 220-221℃；1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.25(s,1H),8.61–8.57(m,1H),8.30(s,1H),8.30–8.25(m,1H),8.05–7.97(m,2H),7.84–7.77(m,1H),7.61(t,J＝8.0Hz,1H),7.57–7.51(m,1H),7.49(d,J＝1.4Hz,1H),7.48(d,J＝5.6Hz,1H),7.18–7.11(m,1H).13C NMR(101MHz,DMSO-d6)δ156.56,155.71,155.02,152.12,144.43,140.04,139.47,134.32,129.65,129.19(d,J＝32.3Hz),128.50,126.48,125.37,124.18(d,J＝272.7Hz),123.66,123.42,120.05,118.86,112.65,105.63.HRMS(ESI)m/z:[M+H]+calcd for C20H13ClF3N5S:448.0605；found:448.0601.
实施例26
5-氯-N2-(4-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物25)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-9。White solid(yield:27％).mp 148-149℃；1H NMR(400MHz,Chloroform-d))δ8.39(s,1H),8.29(d,J＝6.1Hz,1H),8.23(s,1H),8.05(s,1H),7.93–7.90(m,1H),7.71(s,1H),7.38(d,J＝1.7Hz,1H),7.36–7.30(m,1H),7.30(d,J＝1.7Hz,1H),7.29(d,J＝6.0Hz,1H),7.23–7.17(m,1H),7.18(s,1H),7.16–7.10(m,1H).13C NMR(101MHz,DMSO-d6)δ156.86,155.52,155.22,153.73,148.38,143.36,139.48,139.31,129.36,129.14(d,J＝32.3Hz),127.43,126.01,125.72,124.09(d,J＝273.7Hz),123.62,119.86,118.56,114.87,109.56,105.56.HRMS(ESI)m/z:[M+H]+calcd for C20H13ClF3N5S:448.0605；found:448.0604.
实施例27
5-氯-N2-(5-(呋喃-2-基)吡啶-2-基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物26)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-10。White solid(yield:34％).mp 190-191℃；1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.17(s,1H),8.52(s,1H),8.29(d,J＝8.1Hz,1H),8.25(s,1H),8.13(s,1H),7.97(s,1H),7.94(d,J＝8.7Hz,1H),7.75(dd,J＝8.7,2.5Hz,1H),7.72(s,1H),7.57(t,J＝8.0Hz,1H),7.42(d,J＝7.9Hz,1H),6.93(s,1H).13C NMR(101MHz,DMSO-d6)δ157.13,156.12,155.50,152.14,145.28,144.83,139.97,139.32,134.84,130.08,129.75(d,J＝32.4Hz),126.83,125.99(q,J＝272.5),123.27,122.11,120.44(d,J＝3.6Hz),119.15(d,J＝3.6Hz),113.18,108.85,105.91.432.0834.HRMS(ESI)m/z:[M+H]+calcd for C20H13ClF3N5S:432.0833；found:432.0838.
实施例28
5-氯-N2-(3-(噻吩-3-基)苯基)-N4-(3-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物27)的合成：
合成步骤同实施例1，将中间体I-1替换为中间体I-3，将中间体II-1替换为中间体II-11。White solid(yield:23％).mp 128-129℃；1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.14(s,1H),8.23(s,1H),8.13(d,J＝7.7Hz,1H),7.92(d,J＝2.0Hz,1H),7.86(t,J＝1.9Hz,1H),7.60–7.51(m,3H),7.40(dd,J＝13.9,6.2Hz,2H),7.35–7.32(m,1H),7.26(dt,J＝7.7,1.4Hz,1H),7.20(t,J＝7.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ157.70,155.66,155.23,141.66,140.65,139.56,135.38,129.37,129.22(d,J＝30.3Hz),128.82,126.89,126.29,126.05,124.11(d,J＝272.7Hz),120.59,119.87,119.55,118.86,118.08,117.06,104.29.HRMS(ESI)m/z:[M+H]+calcd for C21H14ClF3N4S:447.0653；found:447.0655.
实施例29
5-氯-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(4-(三氟甲氧基)苯基)嘧啶-2,4-二胺(化合物28)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-4。White solid(yield:34％).mp220-221℃；1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),9.11(s,1H),8.67(s,1H),8.26(s,1H),8.05(d,J＝8.8Hz,1H),7.91(dd,J＝14.9,8.9Hz,3H),7.85(s,1H),7.69–7.63(m,1H),7.56(d,J＝5.0Hz,1H),7.37(d,J＝8.4Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.67,155.79,154.79,151.84,145.30,144.17,138.36,137.92,134.76,127.37,125.72,124.85,124.44(2C),122.65(d,J＝229.78Hz),121.23(2C),120.20,112.69,105.37.HRMS(ESI)m/z:[M+H]+calcd for C20H13ClF3N5OS:464.0554；found:464.0557.
实施例30
5-氯-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(3-(三氟甲氧基)苯基)嘧啶-2,4-二胺(化合物29)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-5。White solid(yield:44％).mp178-179℃；1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.14(s,1H),8.69(s,1H),8.29(s,1H),8.02(dd,J＝13.5,8.5Hz,2H),7.97–7.91(m,1H),7.89–7.83(m,2H),7.66(t,J＝4.0Hz,1H),7.57(d,J＝5.1Hz,1H),7.48(t,J＝8.2Hz,1H),7.09(d,J＝8.3Hz,1H).13CNMR(101MHz,DMSO-d6)δ156.65,155.56,154.93,151.79,148.38,145.25,140.46,138.32,134.87,129.94,127.30,125.73,124.91,121.12,120.24,120.14(d,J＝257.12Hz),115.47,114.47,112.79,105.55.HRMS(ESI)m/z:[M+H]+calcd for C20H13ClF3N5OS:464.0554；found:464.0553.
实施例31
5-氯-N4-(4-氟苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)嘧啶-2,4-二胺(化合物30)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-6。White solid(yield:24％).mp233-234℃；1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),9.01(s,1H),8.65(d,J＝2.3Hz,1H),8.23(s,1H),8.03(d,J＝8.7Hz,1H),7.95–7.85(m,2H),7.79(dd,J＝8.8,5.1Hz,2H),7.66(dd,J＝5.2,3.0Hz,1H),7.59(d,J＝5.1Hz,1H),7.23(t,J＝8.6Hz,2H).13CNMR(101MHz,DMSO-d6)δ158.79(d,J＝241.4Hz),156.69,155.94,154.52,151.83,145.26,138.35,134.84,127.27,125.83,125.12(d,J＝8.1Hz,2C),124.80,120.28(2C),115.11,114.89,112.58,105.13.HRMS(ESI)m/z:[M+H]+calcd for C19H13ClFN5S:398.0637；found:398.0641.
实施例32
5-氯-N4-(4-氟-3-(三氟甲基)苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)嘧啶-2,4-二胺(化合物31)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-7。White solid(yield:50％).mp212-213℃；1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.25(s,1H),8.68(d,J＝2.4Hz,1H),8.35–8.30(m,1H),8.28(s,1H),8.04(dd,J＝6.7,2.6Hz,1H),7.99(d,J＝8.7Hz,1H),7.91(dd,J＝8.8,2.4Hz,1H),7.86(d,J＝2.9Hz,1H),7.66(dd,J＝5.1,2.9Hz,1H),7.56(d,J＝5.1Hz,1H),7.51(t,J＝9.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.60,156.13,154.89(d,J＝250.48Hz),154.98,151.72,145.29,138.30,135.40(d,J＝3.0Hz),134.85,129.01(d,J＝8.1Hz),127.31,125.72,124.87,122.60(d,J＝272.7Hz),121.01,120.99,120.24,117.13(d,J＝21.2Hz),116.25(dd,J＝32.4,13.3Hz),112.54,105.32.HRMS(ESI)m/z:[M+H]+calcd for C20H12ClF4N5S:466.0511；found:466.0511.
实施例33
5-氯-N4-(3,4-二氟苯基)-N2-(5-(噻吩-3-基)吡啶-2-基)嘧啶-2,4-二胺(化合物32)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-8。White solid(yield:42％).mp227-228℃；1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.05(s,1H),8.68(s,1H),8.31–8.17(m,2H),8.06–7.85(m,3H),7.71–7.52(m,3H),7.44–7.34(m,1H).13C NMR(101MHz,DMSO-d6)δ156.65,155.41,154.72,151.86,148.85(d,J＝230.8Hz),145.61(d,J＝255.5Hz),145.23,138.34,135.81,134.90,127.32,125.77,124.90,120.29,118.54,116.78(d,J＝18.2Hz),112.84,111.43(d,J＝22.2Hz),105.34.FTMS(ESI):(m/z)calcdC19H12ClF2N5S(M+H):416.053340；found:416.053338.
实施例34
5-氯-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(4-(三氟甲基)苯基)嘧啶-2,4-二胺(化合物33)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-9。White solid(yield:23％).mp232-233℃；1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.23(s,1H),8.69(s,1H),8.31(s,1H),8.14(d,J＝8.4Hz,2H),8.08(d,J＝8.7Hz,1H),7.97(dd,J＝8.7,2.4Hz,1H),7.88(dd,J＝3.0,1.5Hz,1H),7.68(dd,J＝8.2,5.3Hz,3H),7.58(d,J＝5.0Hz,1H).13C NMR(101MHz,DMSO)δ156.64,155.55,155.06,151.82,145.30,142.58,138.34,134.90,133.33,127.36(2C),125.76,125.50,125.49,124.07(d,J＝178.8Hz),122.16(2C),120.28,112.81,105.81.FTMS(ESI):(m/z)calcd C20H13ClF3N5S(M+H):448.059690；found:448.059688.
实施例35
5-氯-N2-(5-(噻吩-3-基)吡啶-2-基)-N4-(4-(三氟甲基)苄基)嘧啶-2,4-二胺(化合物34)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-10。White solid(yield:56％).mp204-205℃；1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.63(s,1H),8.10(d,J＝3.2Hz,2H),7.93(d,J＝8.8Hz,1H),7.90–7.84(m,2H),7.73(d,J＝8.0Hz,2H),7.66(dd,J＝5.0,3.0Hz,1H),7.62(d,J＝8.0Hz,2H),7.56(d,J＝5.1Hz,1H),4.72(d,J＝6.0Hz,2H).13CNMR(101MHz,DMSO)δ157.46,156.97,153.30,151.89,145.22,144.44,138.33,134.75,127.75(2C),127.45(q,J＝30.3Hz),127.29,125.74(t,J＝272.7Hz),125.71,125.23(q,J＝4.0Hz,2C),124.57,120.11,112.11,104.86,43.49.HRMS(ESI)m/z:[M+H]+calcd forC21H15ClF3N5S:462.0762；found:462.0762.
实施例36
叔丁基(4-((5-氯-2-((5-(噻吩-3-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)氨基甲酸酯(化合物35)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-11。White solid(yield:58％).mp213-214℃；1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.38(s,1H),8.95(s,1H),8.64(d,J＝2.5Hz,1H),8.19(s,1H),8.03(d,J＝8.8Hz,1H),7.89–7.83(m,2H),7.69–7.63(m,1H),7.61–7.53(m,3H),7.47(d,J＝8.6Hz,2H),1.51(s,9H).13C NMR(101MHz,DMSO-d6)δ156.67,156.26,154.36,153.05,151.91,145.07,138.44,135.97,134.69,132.75,127.25,125.71,124.60(2C),124.58(2C),119.98,118.51,112.91,104.83,79.00,28.19(3C).FTMS(ESI):(m/z)calcd C19H15ClN6S(M+H):395.083160；found:395.083158.
实施例37
叔丁基(3-((5-氯-2-((5-(噻吩-3-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)氨基甲酸酯(化合物36)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-12。White solid(yield:53％).mp211-212℃；1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.35(s,1H),9.00(s,1H),8.64(d,J＝2.4Hz,1H),8.24(s,1H),8.14(d,J＝8.8Hz,1H),8.06(s,1H),7.93–7.80(m,2H),7.67(t,J＝3.9Hz,1H),7.56(d,J＝5.1Hz,1H),7.34–7.16(m,3H),1.41(s,9H).13CNMR(101MHz,DMSO-d6)δ156.49,156.01,154.58,152.68,151.74,145.14,139.60,138.81,138.37,134.83,128.52,127.26,125.77,124.75,120.15,117.08,113.94,113.37,112.43,105.24,79.08,28.04(3C).FTMS(ESI):(m/z)calcd C19H15ClN6S(M+H):395.083130；found:395.083128.
实施例38
N-(4-((5-氯-2-((5-(噻吩-3-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)苯基)乙酰胺(化合物37)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-13。White solid(yield:44％).mp286-287℃；1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.74(s,1H),8.93(s,1H),8.63(s,1H),8.19(s,1H),8.04(d,J＝8.8Hz,1H),7.94–7.85(m,2H),7.70–7.55(m,9H),2.07(s,3H).13C NMR(101MHz,DMSO-d6)δ168.15,156.67,156.09,154.31,151.91,145.13,138.41,135.69,134.73,133.61,127.28,125.74,124.66,124.02(2C),120.06,119.22(2C),112.74,105.01,23.99.FTMS(ESI):(m/z)calcd C21H17ClN6OS(M+H):437.093810；found:437.093808.
实施例39
5-氯-N4-(吡啶-2-基)-N2-(5-(噻吩-3-基)吡啶-2-基)嘧啶-2,4-二胺(化合物39)的合成：
中间体I-14的合成：2,5-二氯-N-(吡啶-2-基)嘧啶-4-胺
氩气氛围下，将2-吡啶胺(2.12mmol,0.2g)加入到无水THF(5mL)中，将所得溶液在冰浴中冷却至0℃，然后加入NaH(60％,3.13mmol,0.13g)，在室温下搅拌30min后，加入2,4,5-三氯嘧啶(1.77mmol,0.32g)。在室温搅拌反应4小时后，反应体系用20mL水淬灭，用乙酸乙酯(2×30mL)萃取，然后用饱和氯化钠溶液洗涤一次。有机相用无水硫酸钠干燥过夜后浓缩，残留物经自动色谱系统纯化，得到0.09g白色固体(产率：22％)。
剩下合成步骤同实施例1。White solid(yield:27％).mp 234-235℃；1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.70(d,J＝2.4Hz,2H),8.46(d,J＝8.5Hz,1H),8.40(d,J＝4.8Hz,1H),8.35(s,1H),8.16(d,J＝8.5Hz,1H),8.05(dd,J＝8.7,2.5Hz,1H),7.92(d,J＝2.8Hz,1H),7.86(t,J＝8.0Hz,1H),7.67(t,J＝3.7Hz,1H),7.62(d,J＝5.1Hz,1H),7.17(dd,J＝7.3,5.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ156.56,154.88,154.77,151.73,151.41,147.70,145.08,138.33,138.28,135.12,127.28,125.84,125.01,120.39,119.47,115.68,112.91,105.85.FTMS(ESI):(m/z)calcd C18H13ClN6S(M+H):381.067290；found:381.067287.
实施例40
叔丁基4-((5-氯-2-((5-(噻吩-3-基)吡啶-2-基)氨基)嘧啶-4-基)氨基)哌啶-1-羧酸酯(化合物40)的合成：
合成步骤同实施例1，仅将中间体I-1替换为中间体I-15。White solid(yield:58％).mp234-235℃；1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),8.58(s,1H),8.35(d,J＝8.8Hz,1H),8.04(d,J＝4.4Hz,1H),7.91–7.82(m,1H),7.56–7.30(m,4H),5.23(t,J＝6.4Hz,1H),4.24–3.95(m,4H),2.94(t,J＝10.7Hz,2H),2.10(d,J＝12.4Hz,2H),1.47(s,9H).13C NMR(101MHz,Chloroform-d)δ157.26,156.66,154.83,152.22,151.64,144.28,138.56,136.33,127.02,125.85,125.80,120.27,112.84,106.32,79.94,48.80,42.77(2C),31.91(2C),28.57(3C).FTMS(ESI):(m/z)calcd C18H19ClN6S(M+H):387.114290；found:387.114287.
实施例41
体外组织蛋白酶C酶抑制作用评价：
用白色384孔板测定化合物对人重组Cat C酶的抑制作用。在含有25mM HEPES缓冲液、50mM NaCl、5mM MDTT和0.01％(v/v)Tritonx-100(pH5.0)的测定缓冲液中，将人重组Cat C稀释至浓度为5nM。在孔中加入20μL稀释酶(在测定中对应于2nM的Cat C)和10μL被测化合物或阳性对照(AZD7986)，然后在25℃下孵育30min，然后加入20μL底物(h-gly-arg-amc)，最终浓度为100μM。反应60min后，在EXλ350nm和EMλ450nm测定AMC的吸收。以上检测结果用SPSS17.0计算IC50值，结果如下表：
实施例42
体外细胞内组织蛋白酶C酶抑制作用评价：
胞内酶活测定在96孔板中进行。将含有U937或THP-1细胞的30μL PBS细胞悬液加入孔中，使每孔含有3×106个细胞，并在孔中加入AZD7986或被测化合物10μL，在37℃下孵育1h后，加入10μL h-gly-arg-amc(50μM)溶液作为底物，并开始反应，在37℃下进一步孵育1h，测定AMC在EXλ350nm和EMλ450nm处的吸收。以上检测结果用SPSS17.0计算IC50值，结果如表1：
表1
“NT”:未测试，因为在0.2μM的浓度下未检测到化合物对Cat C的抑制作用。
实施例43
体内急性毒性评价：
根据表1中的结果，优选化合物38进行体内活性测试，对ICR小鼠的选择20只ICR小鼠(约一半，约20g，从安徽医科大学动物系购买)，年龄6-8周，进行化合物38的急性毒性试验。将它们随机分为两组并适应性饲养一周。禁食12h后，一次分别口服1500mg/kg(0.5％CMC-Na作为溶剂)化合物38。每天观察并记录小鼠的体重，死亡率和行为学特征，持续一周。随后，将小鼠麻醉并将组织用于HE染色。
急性毒性测试结果为LD50>1500mg/kg，组织器官未见病理改变。
实施例44
本发明化合物38的体内药物代谢动力学研究：
选取7-9周龄雄性SD大鼠20只(SPF级，体重约250g，购自安徽医科大学动物实验中心)进行化合物38的体内药物代谢动力学特征检测，给药方式选择口服和静脉注射。口服给药的化合物38使用0.5％的羧甲基纤维素钠作溶剂，配制成2mg/mL口服工作液；静脉注射给药的化合物38使用10％DMSO+50％PEG400+40％纯水系统作溶剂，配制成1mg/mL静脉注射工作液，有机滤头(0.22μm)过滤，取出20μL，用甲醇定容至10mL进行浓度验证。SD大鼠适应性饲养3天，第三日晚禁食不禁水，第四日给药，给药后两小时正常供食，口服灌胃给药按10mg/kg给药，尾静脉注射给药浓度为2mg/kg。在给药后5,15,30,60,120,240,480和1440min时间点下收集大鼠的血浆。采血用毛细管和EP管等提前用0.1％肝素钠溶液浸润，采出大鼠血液应置于冰上并加入10μL的肝素钠溶液抗凝，采血完成后进行4℃，3000转/min离心15min，取上层血浆送检或保存在-20℃。肺组织和骨髓标本用生理盐水匀浆离心，收集上清液保存。样品中的化合物38用乙腈萃取收集，通过LC-MS/MS测定乙腈中化合物38的含量。使用非房室PK模型分析各项PK参数。不同样品的时间-浓度曲线由Graphpad 6.0进行描绘。图2为本发明中的化合物38在大鼠口服(10mg/kg)给药后的血浆浓度与时间曲线。
如表2所示，本发明中的化合物38显示出较好的药代动力学特性。口服给药(10mg/kg)后，化合物的浓度-时间曲线下面积(AUC0-∞)约为510.88μg/L×h，半衰期(t1/2)为1.79h，最大血药浓度(Cmax)为176.61μg/L。与专利CN112920124A中的化合物41相比，化合物38的生物利用度(F％)显著提高(F＝47.30％)，表明本发明中的化合物38具有较好的口服可利用性。
表2
| NO. | 本发明中的化合物38 | 专利CN112920124A中的化合物41 |
| dose/routes | 10mg/kg(po) | 10mg/kg(po) |
| t<sub>1/2</sub>(h) | 1.79 | 1.56 |
| T<sub>max</sub>(h) | 0.77 | 2.0 |
| MRT(h) | 2.35 | 2.68 |
| C<sub>max</sub>(μg/L) | 176.61 | 83.5 |
| AUC<sub>0-∞</sub>(μg/L×h) | 510.88 | 157.5 |
| F(％) | 47.30 | 16.7 |
实施例45
本发明化合物38的体内组织蛋白酶C和NSPs抑制作用测试。
将C57BL/6小鼠(半性，约20g，购自安徽医科大学动物系)随机分为四组(N＝6)。治疗组的小鼠每天口服2、10和50mg/kg化合物38，共6天。对照组每天两次给予等量的生理盐水，共6天。终止时，抽取骨髓和血液分析Cat C和NSPs的活性。将骨髓和血液裂解物添加到384孔板中。使用不同的合成肽底物用于分析NSPs和Cat C活性。
如图1所示，在骨髓和血液中均观察到Cat C活性和下游NSPs活化的明显剂量依赖性降低。
实施例46
本发明化合物38的体内抗炎活性评估：
化合物38的体内抗炎活性通过急性肺损伤(ALI)小鼠模型进行评估。选取C57BL/6小鼠50只(雄性，约20g，购自安徽医科大学动物实验中心)，随机分为5组：对照组、LPS组、化合物38治疗组(N＝10)进行研究。治疗组的小鼠口服给药化合物38，剂量分别为2，10和50mg/kg。正常组小鼠口服生理盐水。给药后1h，除对照组外，通过气管滴注对小鼠进行LPS(20mg/kg)刺激，48h后处死小鼠。收集骨髓、血液和肺组织，用先前描述的方法检测Cat C和NSPs的水平。ELISA试剂盒(Multi Sciences)测定血清和肺组织中IL-6，TNF-α，IL-10和GM-CSF的水平。通过肺湿/干重量比评估组织水肿情况。
髓过氧化物酶(MPO)是PMN的功能标志物和活化标志物，MPO活性反映了PMN在肺组织中的积累。如图3所示，与对照组相比，模型组小鼠中MPO活性显著增加，化合物38以剂量依赖性方式有效的阻止了LPS诱导的ALI模型中MPO活性增加的趋势。而肺湿/干重比可以评估肺ALI模型中的水肿情况。LPS的刺激增加了模型组小鼠肺湿/干比，同样的，化合物38缓解了这种趋势。更重要的是，化合物38提高了小鼠的存活率。以上结果说明化合物38对ALI模型小鼠具有潜在保护作用。骨髓和血液中Cat C的活性和NSPs的活性结果表明LPS的刺激增加了Cat C和NSPs的活性水平，在骨髓和血液中都观察到Cat C活性和下游NSP活化的明显剂量依赖性降低。
为了评估ALI模型中化合物38对肺的保护作用，对肺组织进行了H&E染色。如图4所示，在模型组中可以观察到显著的促炎改变，包括炎性细胞浸润、肺泡出血和扩张、部分肺泡融合和肺泡结构的破坏。然而化合物38以明显的剂量依赖性方式改善了这些组织病理学变化，这意味着化合物38可以预防肺部病变并在ALI模型中发挥一定的保护作用。模型组的大鼠表现出明显的炎症反应，并伴随着细胞因子水平的明显上调(IL-6，TNF-α和GM-CSF)以及不同组织(血液，肺)中IL-10水平的下调。但是，经化合物38治疗的组，促炎细胞因子(IL-6，TNF-α和GM-CSF)的水平降低，抗炎细胞因子(IL-10)以剂量依赖性方式增加。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (8)
1.一种5-取代的嘧啶二胺类衍生物，其特征在于，如式I所示：
其中，R1选自取代苯基、取代苄基、吡啶基、哌啶基中的任一种基团；
R2选自苯基、吡啶基、取代吡啶基、嘧啶基、吡嗪基、哒嗪基中的任一种基团；
R3选自呋喃基或噻吩基；
R4选自氯、溴、呋喃、1-甲基-1H-吡唑-4-基、1-甲基-1,2,3,6-四氢吡啶-4-基、吡啶基、苯基、取代苯基中的任一种基团。
2.根据权利要求1所述的5-取代的嘧啶二胺类衍生物，其特征在于，所述5-取代的嘧啶二胺类衍生物包括结构如下所示的化合物1-40：
3.如权利要求2所述的5-取代的嘧啶二胺类衍生物的制备方法，其特征在于，包括以下步骤：
(1)将C5取代的2,4-二氯嘧啶类化合物和R1-NH2在四丁基碘化铵或者NaH催化下发生亲核取代反应，得到中间体I；
(2)化合物Br-R2-NH2和噻吩硼酸或呋喃硼酸发生铃木反应，得到中间体II；
(3)中间体I和中间体II经布赫瓦尔德-哈特维希反应，得到本发明的化合物1、18-40；
(4)本发明的化合物1或专利CN112920124A中的化合物64和不同取代的硼酸发生铃木反应，得到本发明的化合物2-17；
反应方程式如下：
4.一种药物组合物，包含权利要求1或2所述的5-取代的嘧啶二胺类衍生物或其药学上可接受的盐。
5.一种药物制剂，包含活性成分和药学上可以接受的赋形剂和/或载体，所述活性成分为权利要求1或2所述的5-取代的嘧啶二胺类衍生物。
6.如权利要求1或2所述的5-取代的嘧啶二胺类衍生物在制备调控组织蛋白酶C催化活性制剂中的应用。
7.如权利要求1或2所述的5-取代的嘧啶二胺类衍生物在制备治疗NSP相关疾病药物中的应用。
8.根据权利要求7所述的应用，其特征在于：所述NSP相关疾病选自急性肺损伤、囊性纤维化、支气管扩张以及关节炎、类风湿性关节炎、败血症、急性胰腺炎、肾炎。
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